DESCRIPTION: To provide more effective aetiology-based strategy for cancer prevention and control, the long-term objectives of this application are to: 1) evaluate the impact of defective cellular responses to DNA damage in human breast cancer risk; 2) understand the genetic and non-genetic modification of DNA-induced responses and cancer susceptibility; 3) identify high-risk populations by using both traditional epidemiological risk factors and laboratory measurements; and 4) reduce breast cancer risk by targeting modifiable risk factors (viz., DNA repair capacity and cell proliferation). The primary objective of the proposed research is to evaluate three specific DNA-damage-inducible responses as biomarkers in breast cancer risk assessment (viz., poly(ADP-ribose) polymerase (PARP), nucleotide excision repair (NER), and cell cycle delay). Data from several small preliminary human studies have suggested that these three biomarkers may play important roles in the carcinogenesis pathway of human breast cancer as follows: 1) PARP plays a critical role in blocking cells from proliferation in response to DNA damage and allowing enough time for DNA repair to complete; 2) NER is the most important repair mechanisms in response to a wide variety of DNA damages; and 3) excessive accumulated unrepaired DNA damage may result in prolonged cell cycle delay and consequently, apoptosis. The secondary objective is to assess the mechanisms involved in the regulation of these three responses to DNA damage by genetic and non-genetic factors. The purpose is to identify individuals at risk through modifiable mechanisms. It may then be possible to devise aetiology-based preventive strategies that are more closely tailored to the specific defects conferring individual risk. This approach may provide unique opportunities in cancer prevention and control, particularly in high risk populations. The proposed study will use a cancer case-control study design with a molecular epidemiological approach. The study subjects include 200 incident breast cancer cases and 200 controls (matched by age and family history of breast cancer). A self-administered questionnaire will be used to collect data on demographic factors, family history of cancer, medication, ionizing radiation exposure, and dietary intake. Mitogen-activated peripheral blood T lymphocytes will be used for all the proposed laboratory measurements.